Spontaneous diabetes in the BB rat model is the only widely available animal model for Insulin Dependent Diabetes Mellitus (IDDM) in that it is the only good example of early-onset, non-obese, insulin-dependent, ketosis-prone diabetes and the only model that shows destructive insulitis closely resembling that seen in humans. The evidence to date strongly suggests that diabetes in this model (as in the human system) is most probably due to immune mechanisms specific for a normal islet cell surface antigen. It is not known, however, what the effector mechanism is or why the BB rats express a defect that allows such effector mechanisms to be expressed. Our preliminary studies would indicate that in order to prevent diabetes by bone marrow ingraftment into neonatal BB rats, a mature T cell (present in the bone marrow) is needed. Furthermore we have shown that irradiation of prediabetic BB rats and reconstitution with bone marrow lacking such T cells not only restores lymphocyte numbers to normal but prevents diabetes from occuring in such recipients. Overall our results suggest a definite role for T cells in prevention of disease and suggest a possible defect in the thymic differentiation leading to an imbalance of regulatory T cell subsets. We propose to determine the exact site of the defect in the BB rat, the effector mechanisms responsible for destructive insulitis, and to clone islet-specific T cells for later use as probes to isolate and characterize the specific antigen involved and for future use as immunotherapeutic agents.